The present invention relates to a method for producing N-acylnitroaniline derivatives and, more specifically, an N-acylnitroaniline derivative of formula (4) as shown below, which is useful as an intermediate in the production of pharmaceutical or agricultural products.
A method for producing an N-acylnitroaniline derivative of formula (4) is known which includes the steps of N-acylation of a nitroaniline compound with an acylating agent, such as di-tert-butyl dicarbonate, in the presence of a base, such as 4-N,N-dimethylaminopyridine or the like, and an N-alkylating reaction of the N-acylated product (Japanese Patent Laid-Open Hei 9-295970 (1997)).
However, the method described above has problems in that the yield is not always satisfactory, and a purification process by crystallization was required in the step of N-acylation since large amounts of impurities are present.
Hence, development of an industrially advantageous production method for producing N-acylnitroaniline derivatives of formulas (1) and (4) has been desired.
According to the present invention, N-acylation of nitroaniline compounds can be selectively conducted by using an alkali metal compound or an alkaline earth metal compound in an amount of about 1.6 moles or more per mol of a nitroaniline, and further derivatization thereafter can proceed smoothly to give a desired N-substituted N-acylnitroaniline derivative in a good yield.
Thus, the present invention provides
a method for producing an N-acylnitroaniline derivative of formula (1); 
xe2x80x83wherein X may be the same or different and each denotes
a hydrogen atom; a halogen atom; an alkyl group; a haloalkyl group; an alkoxy group; a phenylalkyl group; a phenylalkoxyl group;
a phenyl group which may be optionally substituted with a halogen, a nitro group, an alkyl group, an N-alkylacylamino group, an N-aralkylacylamino group or an N,N-dialkylamino group;
a benzoyl group which may be optionally substituted with a halogen atom, a nitro group or an alkyl group,
an alkoxycarbonyl group,
an N-alkylacylamino group, an N-aralkylacylamino group, an alkylthio group, an aralkylthio group, an arylthio group, a formyl group, an N,N-dialkylamino group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or a piperidyl group,
n denotes an integer from 0 to 4, or
Xn, together with the benzene ring to which it is bonded, may form a quinoline, fluorene, or naphthalene group, and
R1 denotes an alkyl group, an alkenyl group, an aryl group, an aralkyl group, an alkoxy group, an aryloxy group or an aralkyloxy group,
which comprises reacting a nitroaniline compound of formula (2); 
xe2x80x83wherein X and n are the same as described above, with an acid anhydride of formula (3a) or an acid chloride of formula (3b): 
xe2x80x83wherein R1 is the same as defined above and Z denotes a halogen atom, in the presence of an alkali metal compound or an alkaline earth metal compound in an amount of about 1.6 moles or more per mol of a nitroaniline compound of formula (1), and
a method for producing an N-acylnitroaniline derivative of formula (4); 
xe2x80x83wherein R1 is the same as defined above and R2 denotes an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group, and X and n denote the same as described above, which comprises reacting the resulting product obtained in the above-described method with a compound of formula (5);
R2xe2x80x94Y
wherein R2 denotes the same as defined above and Y denotes a leaving group.
First, a description will be made to the production method of obtaining N-acylnitroaniline derivative of formula (1).
In the compounds disclosed in the present invention, the halogen atoms denoted by X or Z include fluorine, chlorine, bromine and iodine atoms.
The alkyl group in the haloalkyl group, the alkoxy group, the phenylalkyl group, the alkoxycarbonyl group, the phenylalkoxyl group, the N-alkylacylamino group, the N,N-dialkylamino group, and the alkylthio group include an alkyl group of 1 to 10 carbon atoms.
In the N-aralkylacylamino group and the aralkylthio group, the alkyl moiety include an alkyl groups of 1 to 6 carbon atoms such as a methyl group, an ethyl group, n-propyl group, i-propyl group, t-butyl group, n-butyl group, s-butyl group, n-pentyl group, i-pentyl group, n-hexyl group, or the like.
Examples of the aryl groups in the aralkyl, (C6-C10)aryl group, arylthio and the following aroyl groups include a phenyl group, a naphthyl group and the like. Examples of the arylthio group include a phenylthio group, a naphthylthio group and the like.
Examples of the acyl group of the N-alkylacylamino group and N-aralkylacylamino group include a (C1-C6)alkanoyl or (C6-C10)aroyl group, which may be substituted, for example, with a halogen atom. Specific examples of the acyl group include a formyl group, an acetyl group, a pivaloyl group, a trifluoroacetyl group, a trichloroacetyl group, a benzoyl group, a 2-chlorobenzoyl group, 1- or 2-naphthoyl group and the like. Other examples of acyl groups of N-aralkylacylaminxo group will be apparent to one skilled in the art.
Examples of the optionally substituted alkenyl group include chain, branched or cyclic alkenyl groups of 2 to 10 carbon atoms, which may be substituted with a halogen atom, an alkoxyl group of 1 to 6 carbon atoms, or a halogenoaryl group of 6 to 10 carbon atoms. The halogenoaryl group of 6 to 10 carbon atoms include a phenyl or naphthyl group which is substituted with at least one halogen atom. Specific examples of the halogenoaryl group include a chlorophenyl, dichlorophenyl, bromophenyl, fluorophenyl, difluorophenyl, or iodophenyl group and the like.
Specific examples of the optionally substituted alkenyl group include a vinyl group, a 2,2-dimethylvinyl group, a 1-propenyl group, a 1-butenyl group, a cyclohexenyl group and the like.
Examples of the optionally substituted alkynyl group include an alkynyl group of 2 to 10 carbon atoms, which may be substituted with a halogen atom, an alkoxy group of 1 to 6 carbon atoms, an aryl group of 6 to 10 carbon atoms, a halogenoaryl of 6 to 10 carbon atoms, a trialkyl(C1-C4)silyl group and the like.
Specific examples of the optionally substituted alkynyl group include a trimethylsilylethynyl group, a 1-propynyl group, a 1-butynyl group and the like. The nitroaniline compounds of formula (2) are commercially available or can be produced by known methods.
Specific examples of the nitroaniline compound (2) include
2-nitroaniline, 2-bromo-4,6-dinitroaniline, 6-chloro-2,4-dinitroaniline,
2,4-dinitroaniline, 2,6-dinitroaniline, 2,4-dinitro-5-fluoroaniline,
4-methoxy-2-nitroaniline, 4-ethoxy-2-nitroaniline,
4-amino-3-nitrobenzophenone, 4-amino-3-nitrobenzofluoride
2,6-dinitro-4-methylaniline, 2,4-dichloro-6-nitroaniline,
4,6-dimethyl-2-nitroaniline, 2-methyl-6-nitroaniline,
4,5-dichloro-2-nitroaniline, 5-chloro-2-nitroaniline,
4,5-dimethyl-2-nitroaniline, 5-methyl-2-nitroaniline,
4-fluoro-2-nitroaniline, 4-chloro-2-nitroaniline, 4-methyl-2-nitroaniline,
4,5-difluoro-2-nitroaniline, 2,4-dibromo-6-nitroaniline,
4-amino-3-nitrobenzonitrile,
methyl 4-amino-3-nitrobenzoate, 2-amino-3-nitro-9-fluorenone,
4-benzyloxy-2-nitroaniline, 3,3xe2x80x2-dinitrobenzidine,
2,4-dimethyl-3,6 -dinitroaniline, 2,4-dinitro-6-phenylaniline,
4-methoxy-3-methyl-6-nitroaniline, 3-bromo-4-methoxy-6-nitroaniline,
3-amino-2-nitrofluorene, 5-ethoxy-4-fluoro-2-nitroaniline,
2,4-difluoro-6-nitroaniline, 5-chloro-4-methyl-2-nitroaniline,
4-ethyl-2-nitroaniline, 4-nitroaniline, 2 -bromo-4,6-dinitroaniline,
6-chloro-2,4-dinitroaniline, 2,5-dimethoxy-4-nitroaniline,
2-cyano-4-nitroaniline, 2-methoxy-4-nitroaniline,
2-amino-5-nitrobenzophenone, 2-amino-5-nitrobenzotrifluoride,
2,6-dibromo-4-nitroaniline, 2-chloro-4-nitroaniline,
2,6-dichloro-4-nitroaniline, 2methyl-4-nitroaniline,
5-methoxy-2-methyl-4-nitroaniline, 5-amino-2-nitrobenzotrifluoride,
2-bromo-6-chloro-4-nitroaniline, 2-ethoxy-4-nitroaniline,
2-bromo-4-nitroaniline, 2,5-dichloro-4-nitroaniline,
2,5-dimethyl-4-nitroaniline, 5-nitro-2-biphenylamine,
5-methyl-4-nitro-o-anisidine, 3-chloro-6-methyl-4-nitroaniline,
2-amino-3,5-dinitrobenzonitrile, 6-bromo-2-cyano-4-nitroaniline,
3-chloro-4-nitroaniline, 3-methyl-4-nitroaniline,
4,5-dinitro-2-methylaniline, 5-chloro-2-methoxy-4-nitroaniline,
6-chloro-2-cyano-4-nitroaniline, 3,5-dimethyl-4-nitroaniline,
2-chloro-4-nitro-5-piperidine-4-yl-phenylamine,
2,6-dimethyl-4-nitroaniline, ethyl 2-amino-4-chloro-5-nitrobenzoate,
2-(benzyloxy)-4-nitroaniline, methyl 2-amino-5-nitrobenzoate,
4,6-dinitro-o-toluidine, 3,5-dichloro-4-nitroaniline,
2-sec-butyl-4,6-dinitro-phenylamine,
2-amino-5-nitro-2xe2x80x2-chlorobenzophenone, 2-chloro-6-methyl-4-nitroaniline,
4-nitro-2,5-diethoxyaniline, N-methyl-(2-amino-3-nitro)-acetanilide,
2-amino-5-nitro-4-(p-tolylthio)-anisole, 5-amino-6-nitroquinoline,
2-amino-1-nitronaphthalene, 2-nitro-1-naphthylamine,
1-amino-4-nitronaphthalene, 2-bromo-4-nitro-1-naphthylamine and the like.
The alkali metal compound or the alkaline earth metal compound is preferably alkali metal hydride (e.g., sodium hydride, lithium hydride, potassium hydride or the like) or alkaline earth metal hydrides (e.g., calcium hydride, or the like) and among them, sodium hydride is preferred.
The amount of the alkali metal compound or the alkaline earth metal compound to be used is usually about 1.6 moles or more, preferably 1.8 mole or more, and may be up to 5 moles, per mol of the nitroaniline compound (2) with amount greater than 5 moles being within the scope of the invention.
Examples of the acid anhydride include
an aliphatic acid anhydride having 2 to 10 carbon atoms such as acetic anhydride, propionic anhydride, isovalereic anhydride, pivalic anhydride, or the like,
an unsaturated aliphatic acid anhydride having 3 to 10 carbon atoms such as acrylic acid anhydride or the like,
an aromatic carboxylic acid anhydride, of which the aromatic ring (e.g., phenyl, naphthyl or the like) may be substituted with a halogen atom, a nitro group, an alkyl group having C1 to C4 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, s-butyl or the like) or an alkoxy group having C1 to C4 carbon atoms (e.g., methoxyl, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, s-butoxy or the like), and
a dialkyl dicarbonate including a (C1-C4)dialkyl dicarbonate such as dimethyl bicarbonate, diethyl dicarbonate, di-t-butyl dicarbonate or the like.
Examples of the acyl halide (e.g., fluoride, chloride, bromide or iodide) include:
an aliphatic acid halide having 2 to 10 carbon atoms such as acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride, isovareryl chloride, pivaloyl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride or the like,
an unsaturated aliphatic acid halide having 3 to 10 carbon atoms such as acryloyl chloride, propioloyl chloride, methacryloyl chloride, crotonoyl chloride, isocrotonoyl chloride, 2-pentenoyl chloride, 2-hexenoyl chloride, 2-octenoyl chloride, 2-decenoyl chloride or the like
an aromatic carboxylic acid halide, of which the aromatic ring (e.g., phenyl or naphthyl or the like) may be substituted with a halogen atom, a nitro group, C1 to C4 alkyl group, C1 to C4 alkoxy group such as benzoyl chloride, o-methylbenzoyl chloride, p-t-butylbenzoyl chloride, o-chlorobenzoyl chloride, m-chlorobenzoyl chloride, p-chlorobenzoyl chloride, p-nitrobenzoyl chloride, naphthoyl chloride, or the like,
a (C1-C4)alkyl chlorocarbonate such as methyl chlorocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate, isopropyl chlorocarbonate, isobutyl chlorocarbonate, and
an aralkyl chlorocarbonate such as benzyl chlorocarbonate or the like. Specific examples of the acyl halide include fluoride, bromides and iodides, which correspond to the chlorides as specified above. Among the halides, preferred is the chloride and bromide, more preferred is the chloride.
The amount of the acyl anhydride (3a) or acyl halide (3b) used in the present invention is preferably from about 0.8 to about 1.5 moles, more preferably about 0.9 to about 1.3 moles per mol of the nitroaniline compound (2).
A solvent is preferably used in this reaction, and examples of the solvent that may be used include:
ether solvents such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dimethoxyethane, dioxane, or the like,
polar solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or the like,
aromatic hydrocarbon solvents such as toluene, xylene, benzene or the like,
halogenated hydrocarbon solvents such as chlorobenzenes, and
hydrocarbon solvents such as hexane, heptane and the like.
Preferred are ether solvents such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dimethoxyethane, dioxane and the like and aprotic polar solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or the like. These solvents may be used alone or in a mixture of two or more of them.
The concentration of the N-acylnitroaniline derivative of formula (1) in the solvent is not particularly limited, however the reaction is preferably carried out by controlling the concentration of the N-acylnitroaniline derivative in the solvent so that it is within a range from about 0.1 to about 50% by weight, and preferably is within a range from about 1 to about 20% by weight.
Any suitable reaction temperature may be used in the present invention. Preferably, the reaction temperature is set within a range from a temperature higher than the solidification point of the system to a reflux temperature, and more preferably is within a range from about xe2x88x9210xc2x0 C. to the reflux temperature,
After completion of the reaction, the desired product can be obtained by any suitable conventional technique including adding the reaction solution to water and subjecting the solution to an extraction or concentration method, and purification of the product may be carried out by column chromatography, crystallization, or any other suitable method, if necessary. The reaction solution may be used as it is in a subsequent process to produce a pharmaceutical or an agricultural product.
In the production method of the present invention as described above, the N-acylnitroaniline derivative of formula (2) may be isolated and used for a subsequent reaction step, however, it is preferred from an industrial production process standpoint to react the same, without being isolated, with the compound of formula (5) for producing the N-acylnitroaniline derivative of formula (4).
Next, the production method for producing an N-acylnitroaniline derivative of formula (4) will be described.
With regard to R2 of the compound of formula (5), the optionally substituted alkyl group includes, for example,
an alkyl group of 1 to 10 carbon atoms which may be substituted with at least one group selected from a halogen atom, an alkoxy of 1 to 6 carbon atoms, an (C1-C4)alkoxy- or (C7-C11)aralkyloxy-carbonyl group, an aryl of 6 to 10 carbon atoms, a (C6-C10)halogenoaryl group and the like. The (C6-C10)halogenoaryl group means the same groups as specified for R1 above.
The optionally substituted alkenyl group includes, for example,
an alkenyl group of 2 to 10 carbon atoms which may be substituted with a group selected from a halogen atom, an alkoxy of 1 to 6 carbon atoms, an aryl of 6 to 10 carbon atoms, a halogenoaryl of 6 to 10 carbon atoms and the like.
The optionally substituted alkynyl group includes, for example,
an alkynyl group of 2 to 10 carbon atoms which may be substituted with a group selected from a halogen atom, an alkoxy of 1 to 6 carbon atoms, an aryl of 6 to 10 carbon atoms, a halogenoaryl of 6 to 10 carbon atoms and the like.
The leaving group xe2x80x9cYxe2x80x9d in the compound of formula (5) include a halogen atom, or
an OS(O)2R2 group, wherein R2 represents
an alkoxyl group (e.g., an alkoxy group of 1 to 10 carbon atoms such as methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy or the like),
an alkyl group optionally substituted with a halogen atom (e.g., methyl, ethyl, propyl, trifluoromethyl, chloromethyl, chloroethyl, n-propyl, n-butyl, n-penty, hexyl, heptyl, octyl, nonyl, decyl or the like), or
an aryl group optionally substituted with an alkyl group(e g., C1-C4 alkyl such as methyl, ethyl, propyl, butyl or the like) or a halogen atom (e.g., phenyl, naphthyl, tolyl, chlorophenyl, bromophenyl or the like).
Examples of the halogen atom include chlorine, bromine and iodine.
Specific examples of the compounds of formula (5) suitable for the present invention include, for example,
a haloalkyl group such as methyl chloride, propyl chloride, butyl chloride, methyl bromide, ethyl bromide, propyl bromide, butyl bromide, isobutyl bromide, isopropyl bromide, pentyl bromide, methyl iodide, ethyl iodide, pentyl iodide, isobutyl iodide, isopropyl iodide, isopentyl iodide, cyclohexyl iodide, butyl iodide, propyl iodide, heptyl iodide, and the like
an aralkyl halide such as benzyl bromide, benzyl chloride, or the like,
ethyl bromoacetate, methyl bromoacetate, tert-butyl bromoacetate, benzyl bromoacetate, ethyl iodoacetate,
an alkenyl halide such as allyl chloride, allyl iodide or the like,
a sulfonic acid ester such as alkyl methanesulfonate, alkyl chloromethanesulfonate, alkyl p-toluenesulfonate, alkyl trifluoromethanesulfonate, alkyl nonafluorobutanesulfonate,
a dialkyl sulfate, wherein the alkyl denotes a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, an isobutyl group, or
an alkenyl or aralkyl sulfate such as a diallyl sulfonate, a dibenzyl sulfonate, and the like.
Any suitable amount of the compound of formula (5) may be used in the reaction, and the amount is preferably about 0.8 to about 3 moles, more preferably about 0.9 to about 2 moles, per mol the compound of formula (1).
A solvent is preferably used for this reaction, and examples of the solvent include, for example,
ether solvents such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dimethoxyethane, dioxane, and the like,
aprotic polar solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like,
aromatic hydrocarbon solvents such as toluene, xylene, benzene and the like,
halogenated hydrocarbon solvents such as chlorobenzene, and
hydrocarbon type solvents such as hexane, heptane and the like.
Preferred are ether solvents such as tetrahydrofuran, diethyl ether, tert-butyl methyl ether, dimethoxyethane, dioxane and the like and polar solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like. These solvents may be used alone or in a mixture of two or more of them.
Any suitable reaction temperature may be used in the present invention. Preferably, the reaction temperature is set within a range from a temperature higher than the solidification point of the system to a reflux temperature, and more preferably is within a range from about xe2x88x9210xc2x0 C. to the reflux temperature.
After completion of the reaction, the desired product can be obtained by any suitable conventional technique including extraction and concentration, which are conventional post-treatment processes, and if necessary, purification of the product may be carried out by column chromatography, crystallization, or other method.
According to the present invention, an N-acylnitroaniline derivative can be produced in the industrially advantageous manner.